INVESTIGADORES
RABINOVICH Gabriel Adrian
artículos
Título:
VIRAL INDUCTION AND TARGETED INHIBITION OF GALECTIN-1, IN EBV+ POST-TRANSPLANT LYMPHOPROLIFERATIVE DISORDERS
Autor/es:
OUYANG, YING; JUSZCZYNSKI PRZEMYSLAW; ODONNEL EVAN; ARMANT MYRIAM; RODIG SCOTT; TAKEYAMA KUNIHIKO; MONTI STEFANO; RABINOVICH GABRIEL; KUTOK JEFFERY; RITZ JEROME; SHIPP MARGARET
Revista:
BLOOD, THE JOURNAL OF THE AMERICAN SOCIETY OF HEMATOLOGY - PRINT
Editorial:
AMER SOC HEMATOLOGY
Referencias:
Lugar: Washington; Año: 2011 vol. 117 p. 4315 - 4322
ISSN:
0006-4971
Resumen:
Post-transplant lymphoproliferative disorders (PTLD) are potentially fatal Epstein Barr Virus (EBV)-driven B-cell malignancies that develop in immunocompromised solid organ or hematopoietic stem cell recipients. In PTLD, the expression of EBV latent genes including LMP1 and LMP2A, viral immune evasion strategies, and impaired host immune surveillance foster the proliferation of EBV-transformed B cells. Current PTLD treatment strategies include reduction of immunosuppression, which increases the risk of graft rejection, anti-CD20 treatment, combination chemotherapy and administration of EBV-specific cytotoxic T cells. Herein, we report that EBV-transformed lymphoblastoid B-cell lines (LCLs) and primary PTLDs overexpress galectin-1 (Gal1), a carbohydrate-binding lectin that induces tolerogenic dendritic cells and triggers the selective apoptosis of CD4+ Th1 and Th17 cells and cytotoxic T cells. In transcriptional reporter assays, LMP2A and LMP1 each increased Gal1-driven luciferase expression and the combination of LMP2A and LMP1 was additive. In addition, siRNA-mediated depletion of LMP2A decreased Gal1 protein abundance in EBV-transformed LCLs. Gal1 expression in LCLs was both AP-1 and PI3K-dependent. A newly developed neutralizing Gal1 monoclonal antibody selectively inhibited Gal1-mediated apoptosis of EBV-specific CD8+ T cells. Given the tolerogenic and immunosuppressive function of Gal1, antibody-mediated Gal1 neutralization may represent a novel immunotherapeutic strategy for PTLD and other Gal1-expressing tumors.